1. Field of the Invention
The present invention relates, in general, to torsin genes, preferably, torsinA which encodes the torsion dystonia gene, DYT1. In particular, the present invention relates to nucleic acid molecules coding for the torsin protein; purified torsin proteins and polypeptides; recombinant nucleic acid molecules; cells containing the recombinant nucleic acid molecules; antibodies having binding affinity specifically to torsin proteins and polypeptides; hybridomas containing the antibodies; nucleic acid probes for the detection of nucleic acids encoding torsin proteins; a method of detecting nucleic acids encoding torsin proteins or polypeptides in a sample; kits containing nucleic acid probes or antibodies; bioassays using the nucleic acid sequence, protein or antibodies of this invention to diagnose, assess, or prognose a mammal afflicted with torsion dystonia; therapeutic uses; and methods of preventing torsion dystonia in an animal (preferably, a human).
2. Related Art
Movement disorders constitute a group of human neurologic diseases in which aberrant neurotransmission in the basal ganglia is associated with uncontrollable body movements, such as chorea in Huntington disease, tremor and rigidity in Parkinson disease, and twisting contraction in torsion dystonia. Dystonic symptoms can be secondary to a number of neurologic conditions, and to drug or traumatic injury to the brain, but primary or torsion dystonia is distinguished by lack of other neurologic involvement (Fahn, S., Adv Neurol 50:1-8 (1988); Chutorian, A. H., Acta Neuropediatricia 2:33-45 (1996)) and, in contrast to these other two neurodegenerative diseases, the absence of any distinct neuropathology. The clinical manifestations of dystonia show wide variations in age and site of onset, as well as body regions involved. The prevalence of all forms of primary dystonia is estimated at 3/10,000 in North America (Nutt, J. G. et al., Mov Disord 3: 188-194 (1988)).
Early onset, generalized dystonia is the most disabling form of primary dystonia. Symptoms usually begin in an arm or leg at around 12 yrs (range 4-44 years) and spread to involve other limbs within about 5 years (Bressman, S. B. et al., Annal Neurol 36.771-777 (1994b); Greene, P. et al., Mov Disord 10: 143-152 (1995)). The clinical spectrum of early onset dystonia is similar in all ethnic populations, with highest prevalence in the Ashkenazi Jewish (termed here AJ) population (Zeman, W., & Dyken, P., Psychiatr Neurol Neurochir 10:77-121 (1967); Korczyn, A. D. et al., Ann Neurol 8:387-391 (1980); Eldridge, R., Neurology 20:1-78 (1970)), due to a founder mutation (Ozelius, L. et al., Am. J. Hum. Genet. 50:619-628 (1992); Risch, N. J. et al., Nature Genetics 9:152-159 (1995)). Early onset dystonia follows an autosomal dominant mode of inheritance with 30-40% penetrance (Bressman, S. B. et al., Ann Neurol 26:612-620 (1989); Risch, N. J. et al., Am J Hum Genet 46:533-538 (1990)). The responsible gene in Jewish and non-Jewish families has been mapped to human chromosome 9q34 (Ozelius, L. et al., Neuron 2:1427-1434 (1989); Kramer, P. L. et al., Ann Neurol 27:114-120 (1990) and Kramer, P. et al., Am. J. Hum. Gen. 55:468-475 (1994)). Haplotype analysis of the founder mutation in AJ families placed the DYT1 gene in a 1-2 cM interval centromeric to the ASS locus on chromosome 9 (Ozelius, L. et al., Am. J. Hum. Genet. 50:619-628 (1992)) with highest lod scores obtained with adjacent markers, D9S62a/b and D9S63 (Risch, N. et al., Nature Genetics 9:152-159 (1985)).